The present invention relates to the field of medicine, and in particular to a novel series of compounds as tubulin inhibitors and uses thereof.
The invention further relates to a pharmaceutical composition comprising the compounds.
As the main means of cancer treatment, anti-tumor drugs have made considerable contributions to prolonging the survival time of patients and improving their quality of life. Among them, the drugs acting on microtubules (microtubule inhibitors) have a very important status in oncology drugs. However, the current clinical drugs are accompanied with the following unfavorable problems: poor water solubility, inconvenient drug administration, easy to cause allergic reactions, reduced efficacy caused by serious toxic side effects and acquired resistance, and low production due to the difficulty in synthesis of the complicated chemical structures, which all limit their further use. Therefore, there is an urgent need to find novel tubulin inhibitors, especially small molecule inhibitors with simple structures.
Microtubules are important component of eukaryotic cells and important target for antitumor drugs. Microtubules are a major component in the cytoskeleton and made up of α-tubulin and β-tubulin heterodimers, having the hollow tubular structure characteristics. In addition, there is a γ tubulin, which is not a component of microtubules but participates in the assembly of microtubules.
Microtubules have the dynamic properties of polymerization and depolymerization, and play an important role in cell morphology, cell division, signal transduction and material transport. The microtubules polymerize into a spindle in the early stage of cell division, which in the mitosis pulls the chromosome towards two poles and moves into two daughter cells to complete the cell proliferation. Since microtubules play an extremely important role in cell division, now they have become one of the important targets for antitumor drug research. Tubulin inhibitors acting on microtubule systems have also become a class of effective antitumor drugs.
There are two classification methods for tubulin inhibitors. One is to divide them into two categories based on different functional mechanisms: {circumflex over (1)} tubulin depolymerization agent that inhibits the tubulin polymerization; {circumflex over (2)} tubulin polymerization agent that promotes the tubulin polymerization. Another classification method is to divide them into three categories based on different action sites of tubulin inhibitor on tubulin: {circumflex over (1)} tubulin inhibitors acting on the colchicine site; {circumflex over (2)} tubulin inhibitors acting on the vinblastine site; {circumflex over (3)} tubulin inhibitors acting on the paclitaxel site.
Existing studies have shown that there are three major drug binding sites in tubulins: the taxol-binding site (Taxol site), the vinblastine-binding site (Vinblastine site), and the colchieine-binding site (Colchieine site). Among the three sites, the Colchicine site is valuable for the study of small molecule anti-tumor inhibitors due to the small volume of its binding cavity.
Chinese patent application CN1684955 relates to a compound for the treatment of cancers and fungal infections, dehydrophenylahistins (pinabulin) (Formula II), which can be used as a cell cycle inhibitor, tumor-growth inhibitor or fungal inhibitor.

Chinese patent application CN1934101A relates to the use of the above compound for reducing vascular proliferation and vascular density, acting on tumor blood vessels. But plinabulin, when used alone, has a minor inhibitory effect on tumors and causes a lot of disturbance to the immune system function.